The present invention describes novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory drugs, and novel compositions comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory drug, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The present invention also provides methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflanmatory compounds; treating and/or preventing gastrointestinal disorders; treating inflammatory disease states and disorders; and treating and/or preventing ophthalmic diseases or disorders.
The chemistry and pharmacology of nitroxybutylester ((CH2)4xe2x80x94ONO2) derivatives of several aryl propionic acid nonsteroidal antiinflammatory compounds, including ketoprofen, flurbiprofen, suprofen, indobufen and etodolac, was described in PCT Application No. WO 94/12463. Studies on nitroxybutylester derivatives of flurbiprofen and ketoprofen are also reported in Wallace et al, Gastroenterology, 107:173-179 (1994). See, also, Cuzzolin et al, Pharmacol. Res., 29(1):89-97 (1994); Reuter et al, Life Sci. (USA), 55/1(PL1-PL8) (1994); Reuter et al, Gastroenterology, 106(4):Suppl. A759 (1994); Wallace et al, Eur. J. Pharmacol., 257(3):249-255 (1994); Wallace et al, Gastroenterology, 106(4):Suppl. A208 (1994); and Conforti et al, Agents-Actions, 40(3-4): 176-180 (1993). These publications uniformly examine and rely upon the use of indirectly linked nitrogen dioxide substitutions. U.S. Pat. No. 5,703,073 describes nonsteroidal antiinflammatory compounds containing a nitrogen monoxide group indirectly linked to the nonsteroidal antiinflammatory compound and their protection against gastrointestinal, renal and other toxicities normally induced by nonsteroidal antiinflammatory compounds. The compounds described in U.S. Pat. No. 5,703,073 all contain a heteroatom flanked by a carbonyl group in the form of an ester, amide or thioester in the main chain of the linker.
The use of nonsteroidal antiinflammatory compounds for the treatment and/or prevention of ophthalmic diseases or disorders such as glaucoma, inflammations of the eye and elevation of intraocular pressure has been described. For example, U.S. Pat. No. 5,474,985 describes the use of nonsteroidal antiinflammatory compounds to treat or prevent non-inflammatory induced, elevated intraocular pressure associated with the administration of corticosteroids; U.S. Pat. Nos. 5,674,888 and 5,599,535 describe the use of nonsteroidal antiinflammatory compounds to treat loss of trabecular meshwork resulting from aging, exposure to toxic substances, environmental stresses, such as oxidative or phagocytic injury, or glucocorticoid exposure; U.S. Pat. No. 5,814,655 describes topical ophthalmic compositions comprising nonsteroidal antiinflammatory compounds; Wiederholt et al., Invest. Opthalmol. Vis. Sci., 2515-2520 (1994) describes the use of nitric oxide donors to relax trabecular meshwork and ciliary muscle; Behar-Cohen et al., Invest. Opthalmol. Vis. Sci., describes the use of nitric oxide donors to decrease intraocular pressure.
There is a need in the art for nonsteroidal antiinflammatory compounds that do not have the adverse side effects associated with prior art compounds. There is also a need for new and improved treatments of inflammatory disease states and disorders; and ophthalmic diseases and disorders. The present invention is directed to these, as well as other important ends.
The present invention is based on the discovery that it is possible to link a nitrogen monoxide group (NO), and/or a nitrogen dioxide group (NO2) (i.e., nitrosylated and/or nitrosated group, respectively) to a nonsteroidal antiinflammatory compound and that the resulting compounds have good bioavailibility, possess potent analgesic and antiinflammatory properties and have an unexpectedly reduced potential for producing gastrointestinal lesions (ulcers). The novel compounds also have unexpected properties in the treatment and/or prevention of ophthalmic diseases and disorders.
The present invention is also based on the discovery that it is possible to administer at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound (NSAID) and at least one nitric oxide donor to prevent, reduce, or reverse gastrointestinal, renal, and other toxicities induced by the NSAID. NSAIDs are antiinflammatory, analgesic and antipyretic compounds that act at cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and -2) and as inhibitors of both cyclooxygenase and lipoxygenase. A nitric oxide donor is a compound that contains a nitric oxide moiety and which releases or chemically transfers nitric oxide to another molecule. Nitric oxide donors include, for example, S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, and substrates of the various isozymes of nitric oxide synthase.
One aspect of the present invention provides novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds. The nonsteroidal antiinflammatory compound can be nitrosated and/or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and/or nitrogen. The nonsteroidal antiinflammatory compound can be, for example, an aryl propionic acid, an aryl acetic acid or an enolic anilide. The present invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
Another aspect of the invention provides compositions comprising a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds can be, for example, aryl propionic acids, aryl acetic acids, or enolic anilides. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Yet another aspect of the present invention provides kits comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated NSAID and the nitric oxide donor can be separate components in the kit or can be in the form of a composition.
The present invention also provides methods for treating and/or preventing inflammation, pain and fever; decreasing and/or reversing gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory compounds; and treating and/or preventing gastrointestinal disorders in a patient in need thereof which comprises administering to the patient a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition.
The present invention also provides methods to treat inflammatory disease states and disorders by administering to a patient in need thereof a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one nitric oxide donor. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition. Such inflammatory disease states and disorders include, for example, reperfusion injury to an ischemic organ (e.g., reperfusion injury to the ischemic myocardium), myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejection, organ preservation, a female or male sexual dysfunctions, radiation-induced injury, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, stroke, burn, trauma, acute pancreatitis, pyelonephritis, hepatitis, an autoimmune disease, an immunological disorder, senile dementia, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, Alzheimer""s disease, adult or infantile respiratory disease, carcinogenesis or a hemorrhage in a neonate.
The present invention also provides methods to treat and/or prevent ophthalmic diseases and disorders by administering to a patient in need thereof a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one nitric oxide donor. The ophthalmic diseases and disorders include glaucoma, inflammation of the eye and elevation of intraocular pressure. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition.
These and other aspects of the present invention are explained in detail below.
As used throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
xe2x80x9cGastrointestinal disorderxe2x80x9d refers to any disease or disorder of the upper gastrointestinal tract of a patient including, for example, peptic ulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia, and bleeding peptic ulcers that result, for example, from neurosurgery, head injury, severe body trauma or burns.
xe2x80x9cUpper gastrointestinal tractxe2x80x9d refers to the esophagus, the stomach, the duodenum and the jejunum.
xe2x80x9cUlcersxe2x80x9d refers to lesions of the upper gastrointestinal tract lining that are characterized by loss of tissue. Such ulcers include gastric ulcers, duodenal ulcers and gastritis.
xe2x80x9cNSAIDxe2x80x9d refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase.
xe2x80x9cPatientxe2x80x9d refers to animals, preferably mammals, more preferably humans.
xe2x80x9cTransdermalxe2x80x9d refers to the delivery of a compound by passage through the skin and into the blood stream.
xe2x80x9cTransmucosalxe2x80x9d refers to delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.
xe2x80x9cPenetration enhancementxe2x80x9d or xe2x80x9cpermeation enhancementxe2x80x9d refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound such that the rate at which the compound permeates through the skin or mucosal tissue is increased.
xe2x80x9cCarriersxe2x80x9d or xe2x80x9cvehiclesxe2x80x9d refers to carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
xe2x80x9cNitric oxide adductxe2x80x9d or xe2x80x9cNO adductxe2x80x9d refers to compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO+, NOxe2x88x92, NOxc2x7), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
xe2x80x9cNitric oxide releasingxe2x80x9d or xe2x80x9cnitric oxide donatingxe2x80x9d refers to methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO+, NOxe2x88x92, NOxc2x7), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
xe2x80x9cNitric oxide donorxe2x80x9d or xe2x80x9cNO donorxe2x80x9d refers to compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo. xe2x80x9cNO donorxe2x80x9d also includes compounds that are substrates for nitric oxide synthase.
xe2x80x9cAlkylxe2x80x9d refers to a lower alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein.
xe2x80x9cLower alkylxe2x80x9d refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms). Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
xe2x80x9cHaloalkylxe2x80x9d refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cydoalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein. Exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.
xe2x80x9cAlkenylxe2x80x9d refers to a branched or straight chain C2-C10 hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) which can comprise one or more carbonxe2x80x94carbon double bonds. Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the like.
xe2x80x9cAlkynylxe2x80x9d refers to an unsaturated acyclic C2-C10 hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) which can comprise one or more carbonxe2x80x94carbon triple bonds. Exemplary alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.
xe2x80x9cBridged cycloalkylxe2x80x9d refers to two or more cycloalkyl groups, heterocyclic groups, or a combination thereof fused via adjacent or non-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridged cycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl, 2,6 -dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl, 8-azabicyclo[3,2,1]oct-2-enyl and the like.
xe2x80x9cCycloalkylxe2x80x9d refers to a saturated or unsaturated cyclic hydrocarbon comprising from about 3 to about 8 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta,1,3-dienyl, and the like.
xe2x80x9cHeterocyclic ring or groupxe2x80x9d refers to a saturated or unsaturated cyclic hydrocarbon group having about 2 to about 10 carbon atoms (preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms. The heterocyclic ring or group can be fused to an aromatic hydrocarbon group. Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, oxo, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, amnidyl, ester, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonyl and nitro. Exemplary heterocyclic groups include pyrrolyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, 2-imidazonlinyl, imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4 H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the like.
xe2x80x9cHeterocyclic compoundsxe2x80x9d refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
xe2x80x9cArylxe2x80x9d refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings. Exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like. Aryl groups (including bicylic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, aryl, amidyl, ester, carboxamido, alkylcarboxamido and nitro. Exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and the like.
xe2x80x9cAlkylarylxe2x80x9d refers to an alkyl group, as defined herein, to which is appended an aryl group, as defined herein. Exemplary alkylaryl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.
xe2x80x9cArylalkylxe2x80x9d refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein.
xe2x80x9cCycloalkylalkylxe2x80x9d refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
xe2x80x9cHeterocyclicalkylxe2x80x9d refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
xe2x80x9cArylheterocyclic ringxe2x80x9d refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein. Exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to R50Oxe2x80x94, wherein R50 is an alkyl group, as defined herein. Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, and the like.
xe2x80x9cArylalkoxy or alkoxyarylxe2x80x9d refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein. Exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
xe2x80x9cAlkoxyhaloalkylxe2x80x9d refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkyl groups include 4-methoxy-2-chlorobutyl and the like.
xe2x80x9cCycloalkoxyxe2x80x9d refers to R54Oxe2x80x94, wherein R54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
xe2x80x9cHaloalkoxyxe2x80x9d refers to a haloalkyl group, as defined herein, to which is appended an alkoxy group, as defined herein. Exemplary haloalkyl groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.
xe2x80x9cHydroxyxe2x80x9d refers to xe2x80x94OH.
xe2x80x9cOxoxe2x80x9d refers to xe2x95x90O.
xe2x80x9cOxyxe2x80x9d refers to xe2x80x94Oxe2x88x92R77+ wherein R77 is an organic or inorganic cation.
xe2x80x9cHydroxyalkylxe2x80x9d refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
xe2x80x9cAminoxe2x80x9d refers to xe2x80x94NH2.
xe2x80x9cNitratexe2x80x9d refers to xe2x80x94Oxe2x80x94NO2.
xe2x80x9cNitritexe2x80x9d refers to xe2x80x94Oxe2x80x94NO.
xe2x80x9cThionitratexe2x80x9d refers to xe2x80x94Sxe2x80x94NO2.
xe2x80x9cThionitritexe2x80x9d and xe2x80x9cnitrosothiolxe2x80x9d refer to xe2x80x94Sxe2x80x94NO.
xe2x80x9cNitroxe2x80x9d refers to the group xe2x80x94NO2 and xe2x80x9cnitrosatedxe2x80x9d refers to compounds that have been substituted therewith.
xe2x80x9cNitrosoxe2x80x9d refers to the group xe2x80x94NO and xe2x80x9cnitrosylatedxe2x80x9d refers to compounds that have been substituted therewith.
xe2x80x9cNitrilexe2x80x9d and xe2x80x9ccyanoxe2x80x9d refer to xe2x80x94CN.
xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F).
xe2x80x9cAlkylaminoxe2x80x9d refers to R50NHxe2x80x94, wherein R50 is an alkyl group, as defined herein. Exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
xe2x80x9cArylaminoxe2x80x9d refers to R55NHxe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cDialkylaminoxe2x80x9d refers to R52R53Nxe2x80x94, wherein R52 and R53 are each independently an alkyl group, as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
xe2x80x9cDiarylaminoxe2x80x9d refers to R55R56Nxe2x80x94, wherein R55 and R60 are each independently an aryl group, as defined herein.
xe2x80x9cAlkylarylaminoxe2x80x9d refers to R52R55Nxe2x80x94, wherein R52 is an alkyl group, as defined herein, and R55 is an aryl group, as defined herein.
xe2x80x9cAminoalkylxe2x80x9d refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein.
xe2x80x9cAminoarylxe2x80x9d refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an aryl group, as defined herein.
xe2x80x9cSulfinylxe2x80x9d refers to xe2x80x94S(O)xe2x80x94.
xe2x80x9cSulfonylxe2x80x9d refers to xe2x80x94S(O)2OR58, wherein R58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
xe2x80x9cSulfonic acidxe2x80x9d refers to xe2x80x94S(O)2OR76, wherein R76 is a hydrogen, an organic cation or an inorganic cation.
xe2x80x9cAlkylsulfonic acidxe2x80x9d refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
xe2x80x9cArylsulfonic acidxe2x80x9d refers to an sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
xe2x80x9cSulfonic esterxe2x80x9d refers to xe2x80x94S(O)2OR58, wherein R58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
xe2x80x9cSulfonamidoxe2x80x9d refers to xe2x80x94S(O)2xe2x80x94N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, and R51 and R57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
xe2x80x9cAlkylsulfonamidoxe2x80x9d refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.
xe2x80x9cArylsulfonamidoxe2x80x9d refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.
xe2x80x9cAlkylthioxe2x80x9d refers to R50Sxe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cArylthioxe2x80x9d refers to R55Sxe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cAlkylsulfinylxe2x80x9d refers to R50xe2x80x94S(O)xe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cAlkylsulfonylxe2x80x9d refers to R50xe2x80x94S(O)2xe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cArylsulfinylxe2x80x9d refers to R55xe2x80x94S(O)xe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cArylsulfonylxe2x80x9d refers to R55xe2x80x94S(O)2xe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cAmidylxe2x80x9d refers to R51C(O)N(R57)xe2x80x94 wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
xe2x80x9cEsterxe2x80x9d refers to R51C(O)Oxe2x80x94 wherein R51 is a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
xe2x80x9cCarbamoylxe2x80x9d refers to xe2x80x94Oxe2x80x94C(O)N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
xe2x80x9cCarboxylxe2x80x9d refers to xe2x80x94C(O)OR76 wherein R76 is a hydrogen, an organic cation or an inorganic cation.
xe2x80x9cCarbonylxe2x80x9d refers to xe2x80x94C(O)xe2x80x94.
xe2x80x9cMethanthialxe2x80x9d refers to xe2x80x94C(S)xe2x80x94.
xe2x80x9cThialxe2x80x9d refers to xe2x95x90S.
xe2x80x9cCarboxylic esterxe2x80x9d refers to xe2x80x94C(O)OR58, wherein R58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
xe2x80x9cAlkylcarboxylic acidxe2x80x9d and xe2x80x9calkylcarboxylxe2x80x9d refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.
xe2x80x9cAlkylcarboxylic esterxe2x80x9d refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.
xe2x80x9cArylcarboxylic acidxe2x80x9d refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.
xe2x80x9cArylcarboxylic esterxe2x80x9d refers to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.
xe2x80x9cCarboxamidoxe2x80x9d refers to xe2x80x94C(O)N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, and R51 and R57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
xe2x80x9cAlkylcarboxamidoxe2x80x9d refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
xe2x80x9cArylcarboxamidoxe2x80x9d refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
xe2x80x9cUreaxe2x80x9d refers to xe2x80x94N(R58)xe2x80x94C(O)N(R51)(R57) wherein R51, R57, and R58 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
xe2x80x9cPhosphorylxe2x80x9d refers to xe2x80x94P(R70)(R71)(R72), wherein R70 is a lone pair of electrons, thial or oxo, and R71 and R72 are each independently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or an aryl, as defined herein.
xe2x80x9cSilylxe2x80x9d refers to xe2x80x94Si(R73)(R74)(R75), wherein R73, R74 and R75 are each independently a covalent bond, a lower alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein.
The NSAIDs that are nitrosated and/or nitrosylated in accordance with the invention and/or are included in the compositions of the invention can be any of those known in the art, including those exemplified below.
Despite the introduction of many new drugs, aspirin (acetylsalicylic acid) is still the most widely prescribed antiinflammatory, analgesic and antipyretic compound and is a standard for the comparison and evaluation of all other NSAIDs. Salicylic acid itself is so irritating that it can only be used externally. However, derivatives, particularly salicylate esters and salts, have been prepared which provide ingestible forms of the salicylates which have the desired antiinflammatory and other properties. In addition to aspirin, which is the acetate ester of salicylic acid, are the diflurophenyl derivative (diflunisal) and salicylsalicylic acid (salsalate). Also available are the salts of salicylic acid, principally sodium salicylate. Sodium salicylate and aspirin are the two most commonly used preparations for systemic treatment. Other salicylates include salicylamide, sodium thiosalicylate, choline salicylate and magnesium salicylate. Also available are combinations of choline and magnesium salicylates. Also contemplated for use in the present invention are 5-aminosalicylic acid (mesalamine), salicylazosulfapyridine (sulfasalazine) and methylsalicylate.
Another group of NSAIDs are the pyrazolon derivatives, which include, for example, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone and apazone (azapropazone).
Another group of NSAIDs are the para-aminophenol derivatives, which are the so-called xe2x80x9ccoal tarxe2x80x9d analgesics, including, for example, phenacetin and its active metabolite acetaminophen.
Another group of compounds for use in the present invention include indomethacin, a methylated indole derivative, and the structurally related compound sulindac.
Also contemplated is a group of compounds referred to as the fenamates which are derivatives of N-phenylanthranilic acid. The most well known of these compounds is mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamnic acids. They are used either as the acid or as pharmaceutically acceptable salts.
Another contemplated NSAID is tolmetin which, like the other NSAIDs discussed herein, causes gastric erosion and prolonged bleeding time.
Another group of NSAIDs are the propionic acid derivatives. Principal members of this group are, for example, ibuprofen, naproxen, flurbiprofen, fenoprofen and ketoprofen. Other members of this group, in use or study in countries outside the U.S., include, for example, fenbufen, pirprofen, oxaprozin, indoprofen and tiaprofenic acid.
Also contemplated for use in the present invention are piroxicam and ampiroxicam, oxicam derivatives which are a class of antiinflammatory enolic acids. The other related compounds, tenoxicam and tenidap, can also be used. Another compound that is particularly preferred in the present invention is diclofenac, one of the series of phenylacetic acid derivatives that have been developed as antiinflammatory compounds. Other NSAIDs which are contemplated as suitable in the present invention include etodolac and nabumentone.
Each of the above NSAIDs is described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996.
In one embodiment, the present invention describes nitrosated and/or nitrosylated NSAIDs of Formula (I): 
wherein
Rg is a hydrogen atom or a lower alkyl group;
Rh is: 
n is an integer of 0 or 1;
X is:
(i) -T-Blxe2x80x94Wxe2x80x94Bt-T-NOs;
(ii) -T-Bl-Ly-Bx-T-NOs;
(iii) -T-Bl-W-Bt-Wx-Bk-T-NOs;
(iv) -T-Bl-(C(Rb)(Rc))p-Ex-T-NOs;
(v) -T-Bl-G-Bt-Wz-Bk-Gx-Br-T-NOs;
(vi) -T-Bl-J-Ex-T-NOs; or
(vii) -T-Blxe2x80x94C(Re)xe2x95x90N-Ez-T-NOs;
wherein
s is an integer of 1 or 2;
T at each occurrence is independently a covalent bond, a carbonyl, an oxygen, xe2x80x94S(O)oxe2x80x94 or N(Ra)(Ri)xe2x80x94;
o is an integer from 0 to 2;
Ra is a lone pair of electrons, a hydrogen or an alkyl group;
Ri is a hydrogen, an alkyl group, an aryl group, an alkylcarboxylic acid group, an aryl carboxylic acid group, an alkylcarboxylic ester group, an arylcarboxylic ester group, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, xe2x80x94CH2Cxe2x80x94(T-Q)(Re)(Rf), or xe2x80x94(N2O2xe2x80x94)xe2x88x92xc2x7M+, wherein M+ is an organic or inorganic cation,
L at each occurrence is independently xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, -T-, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an arylheterocyclic ring, or xe2x80x94(CH2CH2O)q;
q is an integer from 1 to 5;
B at each occurrence is independently an alkyl group, an aryl group, xe2x80x94(C(Re)(Rf))pxe2x80x94, a heterocyclic ring, an aryl heterocyclic ring, or xe2x80x94(CH2CH2O)q;
p is an integer from 1 to 10;
Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, -T-NOs, or (C(Re)(Rf))k-T-NORs, or Re and Rf taken together with the carbon atoms to which they are attached are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;
Rb and Rc are each independently a haloalkyl, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a heterocyclic ring, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an arylalkyl, an alkylaryl, a carboxamido, an alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, -T-NOs, or (C(Re)(Rf))k-T-NOs, or Rb and Rc taken together with the carbon atoms to which they are attached are a carbonyl, a methanthial, a heterocyclic ring, a cloalkyl group or a bridged cycloalkyl group;
G is a covalent bond, -T-C(O)xe2x80x94, xe2x80x94C(O)-T- or T;
J is a carbonyl, a phosphoryl or a silyl;
k, l, t and z are each independently an integer from 1 to 3;
y is an integer from 1 to 3;
x and r are each independently an integer from 0 to 3;
E at each occurrence is independently xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, -T-, xe2x80x94(C(Re)(Rf))pxe2x80x94, an alkyl group, an aryl group, a heterocyclic ring, arylheterocyclic ring, or xe2x80x94(CH2CH2O)q;
W is oxygen, xe2x80x94S(O)oxe2x80x94, xe2x80x94N(Ra)(Ri)xe2x80x94, carbonyl, or methanthial;
with the proviso that when Ri is xe2x80x94CH2xe2x80x94C(T-NOs)(Re)(Rf) or xe2x80x94(N2O2)xe2x88x92xc2x7M+, or Rb, Rc, Re or Rf are T-NOs or (C(Re)(Rf))k-T-NOs, then the xe2x80x9c-T-NOsxe2x80x9d subgroup designated in X can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, a heterocyclic ring or an aryl group.
In cases where multiple designations of variables which reside in sequence are chosen as a xe2x80x9ccovalent bondxe2x80x9d or the integer chosen is 0, the intent is to denote a single covalent bond connecting one radical to another. For example, B0 would denote a covalent bond, while B2 denotes (Bxe2x80x94B) and (C(Re)(Rf))2 denotes xe2x80x94C(Re)(Rf)xe2x80x94C(Re)(Rf)xe2x80x94.
Another embodiment of the present invention describes nitrosated and/or nitrosylated NSAIDs of Formula (II): 
wherein
Rk is: 
and X is as defined herein.
Another embodiment of the present invention describes nitrosated and/or nitrosylated NSAIDs of Formula (III) 
wherein
X is as defined herein;
Ri at each occurrence is independently Ri, wherein Ri is as defined herein;
Z is an aryl group; and
A1, A2 and A3 comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and each of A1, A2 and A3 is independently:
(1) Cxe2x80x94Ro, wherein Ro at each occurrence is independently a hydrogen, an alkyl, an alkoxyalkyl, a halogen or a nitro group;
(2) Nxe2x80x94Rp, wherein Rp at each occurrence is independently a covalent bond to an adjacent ring atom in order to render the ring aromatic, a hydrogen, an alkyl, an arylalkyl, an aryl or a heteroaryl group;
(3) a sulfur atom;
(4) an oxygen atom; or
(5) Baxe2x95x90Bb, wherein Ba and Bb are each independently a nitrogen atom or Cxe2x80x94Ro wherein Ro is as defined herein.
Another embodiment of the present invention describes nitrosated and/or nitrosylated NSAIDs of Formula (IV): 
wherein
Rm is an alkyl group or an aryl group; and X, Z, A1, A2 and A3 are as defined herein.
Compounds of the present invention which have one or more asymmetric carbon atoms can exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof.
Another aspect of the present invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes. The compounds of the present invention for Formulas (I), (II), (III) and (IV) can be synthesized by one skilled in the art following the methods and examples described herein. The reactions are performed in solvents appropriate to the reagents and materials used are suitable for the transformations being effected. It is understood by one skilled in the art of organic synthesis that the functionality present in the compound must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to one skilled in the art. The use of sulfur and oxygen protecting groups is well known in the art for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, such as those described by T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, New York (1991), the disclosure of which is incorporated by reference herein in its entirety.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by one skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to one skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Nitroso compounds of Formula (I), wherein Rg and Rh are as defined herein, and an O-nitrosylated NSAID ester in which 2{4-[2-(nitrosooxy)ethyl]piperazinyl} ethan-1-ol is representative of the X group as defined herein may be prepared as described below. An appropriate acid (i.e., Formula (I) where X is substituted with hydroxyl) is converted into the ester by reaction with an appropriate monoprotected diol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of the acid with a chloroformate such as isobutylchloroformate in the presence of a non-nucleophilic base such as triethylamine in an anhydrous inert solvent such as dichloromethane, diethylether or THF. The mixed anhydride is then reacted with the monoprotected alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the monoprotected alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine and a tertiary amine base such as triethyl amine to produce the ester. Alternatively, the acid and monoprotected diol may be coupled to produce the ester by treatment with a dehydration agent such as DCC. Alternatively, the acid may first be converted into an alkali metal salt such as the sodium, potassium or lithium salt, and reacted with an alkyl halide that also contains a protected hydroxyl group in a polar solvent such as DMF to produce the ester. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichlormethane, THF, DMF or acetonitrile produces the compound of Formula (I).
Nitroso compounds of Formula (I), where Rg and Rh are as defined herein, and a S-nitrosylated NSAID ester in which 2-{methyl[2-methyl-2-(nitrosothiol) propyl]amino}ethan-1-ol is representative of the X group as defined herein may be synthesized as described below. An appropriate acid (i.e., Formula (I) where X is substituted with hydroxyl) is converted into the ester by reaction with an appropriate protected thiol containing alcohol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of the acid with a chloroformate such as isobutylchloroformate in the presence of a non-nucelophilic base such as triethylamine in an anhydrous inert solvent such as diethylether or THF. The mixed anhydride is then reacted with the protected thiol-containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamnine pyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the protected thiol containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine and a tertiary amine base such as triethyl amine to produce an ester. Alternatively, the appropriate acid and protected thiol-containing alcohol may be coupled to produce the ester by treatment with a dehydration agent such as DCC. Alternatively, the acid may first be converted into an alkali metal salt such as the sodium, potassium or lithium salt, which is then reacted with an alkyl halide which also contains a protected thiol group in a polar solvent such as DMF to produce the ester. Preferred protecting groups for the thiol moiety are as a thioester such as thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically used to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile produces the compound of Formula (I). Alternatively, a stoichiometric quantity of sodium nitrite in aqueous acid produces the compound of Formula (I).
Nitroso compounds of Formula (II), where Rk is defined herein and a S-nitrosylated NSAID ester in which 2-{methyl[2-methyl-2-(nitrosothiol)propyl] amino}ethan-1-ol is representative of the X group as defined herein may be synthesized as described below. An appropriate acid (i.e., Formula (II) where X is substituted with hydroxyl) is converted into the ester by reaction with an appropriate protected thiol containing alcohol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of the acid with a chloroformate such as isobutylchloroformate in the presence of a non-nucelophilic base such as triethylamine in an anhydrous inert solvent such as diethylether or THF. The mixed anhydride is then reacted with the protected thiol-containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the protected thiol containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine and a tertiary amine base such as triethyl amine to produce an ester. Alternatively, the appropriate acid and protected thiol-containing alcohol may be coupled to produce the ester by treatment with a dehydration agent such as DCC. Alternatively, the acid may first be converted into an alkali metal salt such as the sodium, potassium or lithium salt, which is then reacted with an alkyl halide which also contains a protected thiol group in a polar solvent such as DMF to produce the ester. Preferred protecting groups for the thiol moiety are as a thioester such as thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically used to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile produces the compound of Formula (II). Alternatively, a stoichiometric quantity of sodium nitrite in aqueous acid produces the compound of Formula (II).
Nitroso compounds of Formula (II) where Rk is as defined herein and an O-nitrosylated NSAID ester in which 2{4-[2-(nitrosooxy)ethyl]piperazinyl}ethan-1-ol is representative of the X group as defined herein may be prepared as described below. An appropriate acid (i.e., Formula (II) where X is substituted with hydroxyl) is converted into the ester by reaction with an appropriate monoprotected diol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of the acid with a chloroformate such as isobutylchloroformate in the presence of a non-nucleophilic base such as triethylamine in an anhydrous inert solvent such as dichloromethane, diethylether or THF. The mixed anhydride is then reacted with the monoprotected alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine. Alternatively, the acid may first be converted to the acid chloride with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the monoprotected alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamine pyridine and a tertiary amine base such as triethyl amine to produce the ester. Alternatively, the acid and monoprotected diol may be coupled to produce the ester by treatment with a dehydration agent such as DCC. Alternatively, the acid may first be converted into an alkali metal salt such as the sodium, potassium or lithium salt, and reacted with an alkyl halide that also contains a protected hydroxyl group in a polar solvent such as DMF to produce the ester. Preferred protecting groups for the alcohol moiety are silyl ethers such as trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF or acetonitrile produces the compound of Formula (II).
Nitroso compounds of Formula (III) wherein A1, A2, A3, Ri and Z are as defined herein and an S-nitrosylated enol ester in which 2-{methyl[2-methyl-2-nitrosothiol)propyl] amino} acetyl is representative of the X group as defined herein may be prepared as described below. The enolic form of the xcex2-keto amide of Formula (III) where X is substituted with hydrogen is converted to the ester by reaction with an appropriate protected thiol containing activated acylating agent. Preferred methods for the formation of an enol ester are reacting the enol with the preformed acid chloride or symmetrical anhydride of the protected thiol-containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically used to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile with or without an amine base such as pyridine or triethylamine acid produces the compound of Formula (III). Alternatively, a stoichi metric quantity of sodium nitrite in aqueous acid produces the compound of Formula (III).
Nitroso compounds of Formula (III) wherein A1, A2, A3, Ri and Z are as defined herein and an O-nitrosylated enol ester in which 2-{methyl[2-methyl-2-nitrosooxy)ethyl]amino}acetyl is representative of the X group as defined herein may be prepared as described below. The enolic form of the xcex2-keto amide of Formula (III) where X is substituted by hydrogen is converted to the ester by reaction with an appropriate protected alcohol containing activated acylating agent. Preferred methods for the formation of enol ester are reacting the enol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF or acetonitrile with or without an amine base such as pyridine or triethylamnine produces the compound of Formula (III).
Nitroso compounds of Formula (IV) wherein A1, A2, A3, Rm and Z are as defined herein and an S-nitrosylated enol ester in which 2-{methyl[2-methyl-2-nitrosothiol)propyl]amino}acetyl is representative of the Y group as defined herein may be prepared as described below. The enolic form of the xcex2-keto amide of Formula (IV) where X is substituted with hydrogen is converted to the ester by reaction with an appropriate protected thiol-containing alcohol activated acylating agent. Preferred methods for the formation of an enol ester are reacting the enol with the preformed acid chloride or symmetrical anhydride of the protected thiol-containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically used to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile with or without an amine base such as pyridine or triethylamine acid produces the compound of Formula (IV). Alternatively, a stoichiometric quantity of sodium nitrite in aqueous acid produces the compound of Formula (IV).
Nitroso compounds of Formula (IV) wherein A1, A2, A3, Rm and Z are as defined herein and an O-nitrosylated enol ester in which 2-{methyl[2-methyl-2-nitrosooxy)ethyl]amino}acetyl is representative of the X group as defined herein may be prepared as described below. The enolic form of the xcex2-keto amide of Formula (IV) where X is substituted by hydrogen is converted to the ester by reaction with an appropriate protected alcohol containing activated acylating agent. Preferred methods for the formation of enol ester are reacting the enol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF or acetonitrile with or without an amine base such as pyridine or triethylamine produces the compound of Formula (IV).
The compounds of the present invention include NSAIDs, including those described herein, which have been nitrosated and/or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfflydryl condensation), carbon and/or nitrogen. The nitrosated and/or nitrosylated NSAIDs of the present invention donate, transfer or release a biologically active form of nitrogen monoxide (i.e., nitric oxide).
Nitrogen monoxide can exist in three forms: NOxe2x88x92 (nitroxyl), NOxc2x7 (uncharged nitric oxide) and NO+ (nitrosonium). NOxc2x7 is a highly reactive short-lived species that is potentially toxic to cells. This is critical because the pharmacological efficacy of NO depends upon the form in which it is delivered. In contrast to the nitric oxide radical (NOxc2x7), nitrosonium (NO+) does not react with O2 or O2xe2x88x92 species, and functionalities capable of transferring and/or releasing NO+ and NOxe2x88x92 are also resistant to decomposition in the presence of many redox metals. Consequently, administration of charged NO equivalents (positive and/or negative) is a more effective means of delivering a biologically active NO to the desired site of action.
Compounds contemplated for use in the present invention (e.g., nitrosated and/or nitrosylated NSAIDs) are, optionally, used in combination with nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer a biologically active form of nitrogen monoxide to a site of its intended activity, such as on a cell membrane in vivo.
The term xe2x80x9cnitric oxidexe2x80x9d encompasses uncharged nitric oxide (NO) and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO+) and nitroxyl ion (NOxe2x88x92). The reactive form of nitric oxide can be provided by gaseous nitric oxide. The nitrogen monoxide releasing, delivering or transferring compounds have the structure F-NO, wherein F is a nitrogen monoxide releasing, delivering or transferring moiety, and include any and all such compounds which provide nitrogen monoxide to its intended site of action in a form active for its intended purpose. The term xe2x80x9cNO adductsxe2x80x9d encompasses any nitrogen monoxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, nitrites, nitrates, S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amnides, nitrosoamines, furoxans as well as substrates for the endogenous enzymes which synthesize nitric oxide. The xe2x80x9cNO adductsxe2x80x9d can be mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/or poly-nitrosated at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
One group of NO adducts is the S-nitrosothiols, which are compounds that include at least one xe2x80x94Sxe2x80x94NO group. These compounds include S-nitroso-polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds. S-nitrosothiols and methods for preparing them are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of each of which are incorporated by reference herein in their entirety.
Another embodiment of the present invention is S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof. Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine and S-nitroso-glutathione.
Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines. Such nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers in the protein are modified.
Other examples of suitable S-nitrosothiols include:
(i) HS(C(Re)(Rf))mSNO;
(ii) ONS(C(Re)(Rf))mRe; and
(iii) H2Nxe2x80x94CH(CO2H)-(CH2)mxe2x80x94C(O)NHxe2x80x94CH(CH2SNO)xe2x80x94C(O)NHxe2x80x94CH2xe2x80x94CO2H;
wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, or -T-Q; or Re and Rf taken together are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is xe2x80x94NO or xe2x80x94NO2; and T is independently a covalent bond, a carbonyl, an oxygen, xe2x80x94S(O)oxe2x80x94 or xe2x80x94N(Ra)RIxe2x80x94, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, xe2x80x94CH2xe2x80x94C(T-Q)(Re)(Rf), or xe2x80x94(N2O2xe2x80x94)xe2x88x92xc2x7M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is xe2x80x94CH2xe2x80x94C(T-Q)(Re)(Rf) or xe2x80x94(N2O2xe2x80x94)xc2x7M+; then xe2x80x9c-T-Qxe2x80x9d can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
In cases where Re and Rf are a heterocyclic ring or taken together Re and Rf are a heterocyclic ring, then Ri can be a substituent on any disubstituted nitrogen contained within the radical wherein Ri is as defined herein.
Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO2 under acidic conditions (pH is about 2.5) which yields the S-nitroso derivative. Acids which can be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids. The thiol precursor can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate in an inert solvent.
Another group of NO adducts for use in the present invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 group. Preferred among these compounds are O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-sugars; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbons; and O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 heterocyclic compounds. Preferred examples of compounds comprising at least one O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and proparylnitrate.
Another group of NO adducts are N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R1R2xe2x80x94N(O-M+)xe2x80x94NO, where R1 and R2 are each independently a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and where M+ is an organic or inorganic cation, such as, for example, an alkyl substituted ammonium cation or a Group I metal cation.
Another group of NO adducts are thionitrates that donate, transfer or release nitric oxide and are represented by the formula: R1xe2x80x94(S)xe2x80x94NO2, where R1 is a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group. Preferred are those compounds where R1 is a polypeptide or hydrocarbon with a pair or pairs of thiols that are sufficiently structurally proximate, i.e., vicinal, that the pair of thiols will be reduced to a disulfide. Compounds which form disulfide species release nitroxyl ion (NOxe2x88x92) and uncharged nitric oxide (NOxc2x7). Compounds where the thiol groups are not sufficiently close to form disulfide bridges generally provide nitric oxide as the NOxe2x88x92 form and not as the uncharged NOxc2x7 form.
The present invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are substrates for nitric oxide synthase. Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine or glutamine, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxide synthase, cytokines, adenosin, bradykinin, calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).
The present invention is also based on the discovery that the administration of a therapeutically effective amount of the compounds and compositions described herein is effective for treating inflammation, pain and fever. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated NSAID of the present invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated NSAID, and, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The compounds can be administered separately or in the form of a composition.
Another aspect of the invention provides methods to decrease or reverse gastrointestinal, renal and other toxicity (such as, for example, kidney toxicity) resulting from the use of nonsteroidal antiinflammatory drugs by administering to a patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition.
Another aspect of the invention provides methods for decreasing and/or preventing gastrointestinal disorders by administering to the patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition. Such gastrointestinal disorders include, for example, peptic ulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia, and bleeding peptic ulcers that result, for example, from neurosurgery, head injury, severe body trauma or burns.
Another aspect of the invention provides methods for treating inflammatory disease states and disorders by administering to the patient in need thereof a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one nitric oxide donor. Such inflammatory disease states and disorders include, for example, reperfusion injury to an ischemic organ (e.g., reperfusion injury to the ischemic myocardium), myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejection, organ preservation, a female or male sexual dysfunction, radiation-induced injury, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, stroke, bur, trauma, acute pancreatitis, pyelonephritis, hepatitis, an autoimmune diseases, an immunological disorder, senile dementia, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, Alzheimer""s disease, adult or infantile respiratory disease, carcinogenesis or a hemorrhage in a neonate. The compounds and compositions of the present invention can also be administered in combination with other medications used for the treatment of these disorders.
Another aspect of the invention provides methods for treating and/or preventing ophthalmic diseases and disorders in a patient by administering to the patient a therapeutically effect amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and optionally at least one nitric oxide donor. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition. Such ophthalmic diseases and disorders include, for example, glaucoma, inflammation of the eye and elevation of intraocular pressure.
When administered in vivo, the compounds and compositions of the present invention can be administered in combination with pharmaceutically acceptable carriers and in dosages described herein. When the compounds and compositions of the present invention are administered as a mixture of at least one nitrosated and/or nitrosylated NSAID and at least one nitric oxide donor, they can also be used in combination with one or more additional compounds which are known to be effective against the specific disease state targeted for treatment. The nitric oxide donors and/or other additional compounds can be administered simultaneously with, subsequently to, or prior to administration of the nitrosated and/or nitrosylated NSAID.
The compounds and compositions of the present invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection, transdermally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Transdermal compound administration, which is known to one skilled in the art, involves the delivery of pharmaceutical compounds via percutaneous passage of the compound into the systemic circulation of the patient. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Other components can be incorporated into the transdermal patches as well. For example, compositions and/or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like. Dosage forms for topical administration of the compounds and compositions can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, and the like. In such dosage forms, the compositions of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. In addition, the compositions can contain polyethylene glycol 400. They can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox II (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol). Woven pads or rolls of bandaging material, e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application. The compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
Solid dosage forms for oral administration can include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets, and pills, the dosage forms can also comprise buffering agents. Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the present invention and vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin. Tablets and pills can be prepared with enteric coatings.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Suppositories for vaginal or rectal administration of the compounds and compositions of the invention, such as for treating pediatric fever and the like, can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer""s solution, and isotonic sodium chloride solution. Sterile fixed oils are also conventionally used as a solvent or suspending medium.
The compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentoethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like. The pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension may also contain stabilizers.
The composition, if desired, can also contain minor amounts of wetting agents, emulsifying agents and/or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
Various delivery systems are known and can be used to administer the compounds or compositions of the present invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like.
The bioavailabilty of the compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
The compounds and compositions of the present invention can be formulated as neutral or pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include, for example, those formed with free amino groups such as those derived from hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, citric, benzoic, fumaric, glutamic, lactic, malic, maleic, nitric, succinic, tartaric p-toluene-sulfonic, methanesulfonic, acids, gluconic acid, and the like, and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to the amount of the nitrosated and/or nitrosylated NSAID and nitric oxide donor that is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of each of the compounds and compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the composition, and which can be adjusted by one of ordinary skill in the art will vary, depending on the age, health, physical condition, sex, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction or disease.
The amount of a given nitrosated and/or nitrosylated NSAID which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician""s Desk Reference, Medical Economics Company, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, Mo., 1993. The precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided by the physician and the patient""s circumstances.
The amount of nitric oxide donor in a pharmaceutical composition can be in amounts of about 0.1 to about 10 times the molar equivalent of the NSAID. The usual daily doses of NSAIDs are about 3 to about 40 mg/kg of body weight and the doses of nitric oxide donors in the pharmaceutical composition can be in amounts of about 1 to about 500 mg/kg of body weight daily, preferably about 1 to about 50 mg/kg of body weight daily. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician""s Desk Reference, supra.
The present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the present invention, including, at least, one or more of the nitrosated and/or nitrosylated NSAIDs described herein and one or more of the NO donors described herein. Associated with such kits can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.